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Introduction: Insulin efsitora alfa (efsitora) is a basal insulin with a flat pharmacokinetic profile and long half-life, enabling weekly dosing. These attributes may provide stable glucose levels. This exploratory phase 1 study aimed to assess the hypoglycemic risk during experimental conditions that mimic situations encountered in daily life. Methods: This was a single-site, open-label, two-period, fixed-sequence study in participants with type 2 diabetes (T2D) previously treated with basal insulin. The incidence, duration, and nadir glucose of hypoglycemia were assessed after treatment with efsitora versus insulin glargine (glargine) during three provocation conditions: 24-h prolonged fasting, prolonged fasting with exercise, and double dosing of study insulin. Results: The 54 enrolled adults (BMI 21.8–39.7 kg/m2, HbA1c 6.5–9.4%) achieved stable fasting glucose before undergoing provocation. Most hypoglycemic events were level 1 (≥ 54 to < 70 mg/dL) and resolved spontaneously or after oral glucose. The incidences of level 1 hypoglycemia for efsitora and glargine were not significantly different: for prolonged fasting, the incidences were 44.7 vs. 42.6% and the difference in proportion was 2.1% (95% CI: – 17.2, 21.4); for prolonged fasting with exercise, the corresponding values were 65.9 vs. 50.0% and 15.9% (– 3.0, 34.8); for double dosing, the corresponding values were 68.1 vs. 61.7% and 6.4% (– 12.8, 25.6). Level 2 hypoglycemia (< 54 mg/dL) was infrequent during both treatments and all provocations. No severe hypoglycemia was observed. Mean nadir glucose (range 62.8–66.3 mg/dL) and hypoglycemia duration (range 76.6–115.2 min) were also similar for the two treatments, depending on the provocation. Conclusion: Overall, weekly efsitora did not increase the incidence, duration, or severity of hypoglycemia compared to daily glargine during provocation periods in patients with T2D. Trial Registration: ClinicalTrials.gov identifier NCT04957914. [ABSTRACT FROM AUTHOR]

Introduction: We assessed the effect of the prandial state on the pharmacokinetics, safety, and tolerability of single and multiple doses of orforglipron (LY3502970), an oral, non-peptide glucagon-like peptide 1 receptor agonist (GLP-1 RA), in two studies (A and B). Methods: Study A and study B were phase 1, randomized, crossover studies in healthy adults aged 18–65 years and 21–70 years, respectively. Participants received single (3 mg, study A) or multiple (16 mg, study B) oral doses of orforglipron under fasted and fed conditions. Blood samples were collected pre- and postdose to assess area under the concentration–time curve (AUC), maximum observed drug concentration (Cmax), time of Cmax (tmax), and half-life (t1/2) associated with terminal rate constant. AUC and Cmax were analyzed using a linear mixed-effects model. Treatment differences were presented as ratios of geometric least squares means (GLSM). Treatment-emergent adverse events (TEAEs), adverse events of special interest, and serious adverse events were assessed. Results: Study A included 12 participants (mean age 45.0 years; male 66.7%); study B included 34 participants (mean age 42.8 years; male 88.2%). GLSM AUC and Cmax were lower by 23.7% and 23.2% in study A, and 17.6% and 20.9% in study B, in the fed versus fasted states, respectively. In both studies, t1/2 and median tmax were comparable between fed and fasted states. The majority of TEAEs in both studies were gastrointestinal tract-related conditions. No serious adverse events or deaths were reported in either study. Conclusion: The observed pharmacokinetic differences due to the prandial state are unlikely to contribute to clinically meaningful differences in the efficacy of orforglipron. The safety profile was consistent with the known profiles of other GLP-1 RAs. Given the absence of prandial restrictions, orforglipron may emerge as a convenient oral treatment option for patients with type 2 diabetes or obesity. Trial Registration: ClinicalTrials.gov identifiers, NCT03929744 and NCT05110794. [ABSTRACT FROM AUTHOR]

Aim: To report the results of a Phase 1b trial evaluating the safety, pharmacokinetics and pharmacodynamics of orforglipron (LY3502970), an oral, non‐peptide glucagon‐like peptide‐1 receptor agonist (GLP‐1RA), in patients with type 2 diabetes (T2D). Materials and Methods: This was a double‐blind, placebo‐controlled Phase 1 study evaluating five different dosing regimens. The first group established that weekly dose escalation of the daily doses of orforglipron was generally well tolerated. This enabled a parallel‐arm design for the four groups following. Participants were randomized 3:1 to daily doses of orforglipron or placebo for 12 weeks. Eligible participants with T2D were aged 18 to 70 years and had glycated haemoglobin (HbA1c) levels ≥53.0 mmol/mol (7.0%) and ≤91.3 mmol/mol (10.5%). Results: A total of 51 participants received orforglipron and 17 received placebo. In the placebo and orforglipron groups, respectively, baseline HbA1c was 8.1% and 8.0%, and baseline body weight was 90.3 and 88.4 kg. The most common adverse events were gastrointestinal‐related, and occurred early in treatment, similar to findings with other GLP‐1RAs. At Week 12, mean t1/2 ranged from 29 to 49 hours. Mean HbA1c change ranged from −1.5% to −1.8% across orforglipron doses, versus −0.4% with placebo, and body weight change was −0.24 to −5.8 kg across orforglipron doses, versus 0.5 kg with placebo. Conclusions: Orforglipron treatment resulted in meaningful reductions in HbA1c and body weight, with an adverse event profile consistent with that of other GLP‐1RAs. Orforglipron may provide a safe and effective once‐daily oral treatment alternative to injectable GLP‐1RAs or peptide oral formulations without water and food restrictions. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate the effects of tirzepatide on body composition, appetite, and energy intake to address the potential mechanisms involved in body weight loss with tirzepatide. RESEARCH DESIGN AND METHODS: In a secondary analysis of a randomized, double-blind, parallel-arm study, the effects of tirzepatide 15 mg (N = 45), semaglutide 1 mg (N = 44), and placebo (N = 28) on body weight and composition, appetite, and energy intake were assessed at baseline and week 28. RESULTS: Tirzepatide treatment demonstrated significant reductions in body weight compared with placebo and semaglutide, resulting in greater fat mass reduction. Tirzepatide and semaglutide significantly reduced appetite versus placebo. Appetite scores and energy intake reductions did not differ between tirzepatide and semaglutide. CONCLUSIONS: Differences in energy intake during ad libitum lunch were not sufficient to explain the different weight outcomes. Further evaluation is needed to assess mechanistic differences related to tirzepatide actions on 24-h energy intake, substrate utilization, and energy expenditure. [ABSTRACT FROM AUTHOR]

Aim: To assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of basal insulin Fc (BIF; LY3209590), a fusion protein combining a novel single‐chain insulin variant together with human IgG2 Fc domain, following single and multiple once‐weekly BIF administration. Materials and Methods: The single ascending dose, 15‐day study assessed four BIF doses (5‐35 mg) in healthy participants and people with type 2 diabetes (T2D). In the 6‐week multiple ascending dose study, people with T2D, previously treated with basal insulin, received insulin glargine daily or a one‐time loading dose of BIF followed by 5 weeks of once‐weekly dosing (1‐10 mg). Safety, tolerability and PK and glucose PD were examined. Results: Mean ages of people with T2D (N = 57) and healthy participants (N = 16) in the single‐dose study were 58.4 and 35.8 years, respectively; mean body mass index values were 29.5 and 26.1 kg/m2. BIF had a PK half‐life of approximately 17 days, which led to a sustained, dose‐dependent decrease in fasting blood glucose for 5 days or longer. No severe hypoglycaemia was observed. The 6‐week ascending dose study included 33 people with T2D aged 40‐69 years. BIF showed a low peak‐to‐trough ratio of 1.14 after the last dose at week 6 (steady state). Over 6 weeks, BIF seven‐point glucose profiles remained constant and were similar to insulin glargine. Rates and duration of BIF hypoglycaemic events were similar to insulin glargine. Conclusions: BIF was well tolerated and the PK/PD profile enabled once‐weekly dosing with minimal variation in exposure in a treatment interval of 1 week. The findings suggest BIF is suitable for further development as a weekly basal insulin in people with diabetes. [ABSTRACT FROM AUTHOR]

This document is a clarification letter regarding a study on a novel oral non-peptide glucagon-like peptide-1 receptor agonist called Orforglipron. The authors explain that there are differences between the body weight change values shown in Figure 3 of the main manuscript and the implied weight change values indicated in Table S3. These differences are due to variations in the analysis model used. The authors recommend that readers interpret the treatment effects based on the change from baseline analysis presented in Figure 3. [Extracted from the article]

Orforglipron, an oral, non-peptide glucagon-like peptide-1 (GLP-1) receptor agonist, is in development for type 2 diabetes and obesity. We assessed the efficacy and safety of orforglipron versus placebo or dulaglutide in participants with type 2 diabetes. In this 26-week, phase 2, double-blind, randomised, multicentre study, participants were recruited from 45 centres (private clinics, hospitals, and research centers) in the USA, Hungary, Poland, and Slovakia. Adult participants aged 18 years or older with type 2 diabetes treated with diet and exercise, with or without metformin, and with a glycated haemoglobin (HbA 1c) of 7·0–10·5%, and stable BMI of 23 kg/m2 or more, were randomly assigned (5:5:5:5:5:3:3:3:3) via an interactive web-response system to placebo, dulaglutide 1·5 mg once per week, or orforglipron 3 mg, 12 mg, 24 mg, 36 mg (group 1), 36 mg (group 2), 45 mg (group 1), or 45 mg (group 2) once per day with no food or water restrictions. Two different dose escalation regimens were evaluated for each of the 36 mg and 45 mg cohorts. Participants were masked to the study drug, dulaglutide, and placebo. The primary efficacy outcome The primary efficacy outcome was mean change in HbA 1c from baseline with orforglipron versus placebo at week 26. Efficacy was analysed in all randomly assigned participants who received at least one dose of study drug and excluded data after the permanent discontinuation of study drug or initiation of rescue medication. Safety was analysed in all participants who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT05048719) and is completed. Between Sept 15, 2021, and Sept 30, 2022, 569 participants were screened and 383 were enrolled and randomly assigned to a group. 352 (92%) completed the study and 303 (79%) completed 26 weeks of treatment. At baseline, the mean age was 58·9 years, HbA 1c was 8·1%, BMI was 35·2 kg/m2, 226 (59%) were men, and 157 (41%) were women. At week 26, mean change in HbA 1c with orforglipron was up to –2·10% (–1·67% placebo adjusted), versus –0·43% with placebo and –1·10% with dulaglutide. HbA 1c reduction was statistically superior with orforglipron versus placebo (estimated treatment difference –0·8% to –1·7%). Change in mean bodyweight at week 26 was up to –10·1 kg (95% CI –11·5 to –8·7; 7·9 kg placebo adjusted [–9·9 to –5·9]) with orforglipron versus –2·2 kg (–3·6 to –0·7) for placebo and –3·9 kg (–5·3 to –2·4) for dulaglutide. The incidence of treatment-emergent adverse events ranged from 61·8% to 88·9% in orforglipron-treated participants, compared with 61·8% with placebo and 56·0% with dulaglutide. The majority were gastrointestinal events (44·1% to 70·4% with orforglipron, 18·2% with placebo, and 34·0% with dulaglutide) of mild to moderate severity. Three participants receiving orforglipron and one participant receiving dulaglutide had clinically significant (<54 mg/dL [<3 mmol/L]) hypoglycaemia and no participants had severe hypoglycaemia. One death occurred in the placebo group and was not related to study treatment. In this phase 2 trial the novel, oral, non-peptide GLP-1 receptor agonist orforglipron at doses of 12 mg or greater showed significant reductions in HbA 1c and bodyweight compared with placebo or dulaglutide. The adverse event profile was similar to other GLP-1 receptor agonists in similar stage of development. Orforglipron might provide an alternative to injectable GLP-1 receptor agonists and oral semaglutide, with the prospect of less burdensome administration to achieve treatment goals in people with type 2 diabetes. Eli Lilly and Company. [ABSTRACT FROM AUTHOR]